Aim: To compare the analgesic efficacy of intrathecal morphine and fentanyl as an adjuvant to isobaric ropivacaine in patients undergoing lower segment caesarean section under spinal anesthesia. Materials and Methods: A total of 120 parturients aged between 20 and 35 years of age, belonging to American Society of Anaesthesiologist (ASA) physical status I and II, were randomized into two groups: Group M received 15 mg of 0.75% isobaric ropivacaine (2 mL) and 100 μg of morphine (1 mL) intrathecally; and Group F received 15 mg of 0.75% isobaric ropivacaine (2 mL) and 25 μg of fentanyl (0.5 mL) and 0.5 mL of normal saline intrathecally. The primary outcome was the duration of postoperative analgesia. Block characteristics, hemodynamic variables, demand for rescue analgesia, and adverse effects were also assessed. Results: The demographic profiles and block characteristics were comparable in all groups. The mean duration of analgesia in Group M and Group F was 996.03 ± 25.3 and 203.88 ± 25.20 min, respectively; the difference between the groups was highly significant (P < 0.0001). Lesser visual analog scale pain scores were observed in Group M after the fourth postoperative hour and continued till 24 h (P < 0.05 at time interval of 4, 6, 8, 12, and 24 h). Conclusion: The addition of intrathecal morphine to isobaric ropivacaine resulted in a longer duration of postoperative analgesia as compared to intrathecal fentanyl in parturients undergoing caesarean section under spinal anesthesia.

The number of caesarean sections is increasing progressively in the Indian subcontinent. Since first reported by Karl August Bier in 1898, spinal anesthesia remains a popular and safe choice for providing anesthesia in lower segment caesarean section (LSCS). Ropivacaine, a pure S-enantiomer form of racemic bupivacaine, is becoming the drug of choice for spinal anesthesia as it shares physicochemical properties with bupivacaine along with added advantage of less systemic toxicity and greater margin of safety. Its low lipid solubility leads to greater sensory–motor differentiation by blocking sensory fibers more readily in comparison to motor fibers. Early recovery of motor functions is associated with decreased incidences of venous thromboembolism and shorter hospital stay. Augmentation of the effect of intrathecal local anesthetics (LA) by addition of intrathecal opioids is a well-known practice as opioids act synergistically with LA to potentiate sensory block without affecting sympathetic blockade. Intrathecal opioids decrease dose of LA, enhance anesthesia, and provide prolonged postoperative analgesia without increasing adverse effects.

Small doses of opioids administered to the central nervous system provide adequate analgesia, reducing the side effects of intravenous (IV) analgesic administration. Pruritus, nausea and vomiting, or respiratory depression are some examples.[1] This adjuvant analgesic technique is expected to decrease postoperative pain intensity and opioid requirements and to speed up recovery. Intrathecal morphine, which is less hydrophobic than other opioids, has a longer residence time in the cerebrospinal fluid (CSF) and provides excellent postoperative analgesia.[2] According to experimental studies, intrathecally administered fentanyl is cleared from the CSF within a relatively short distance, whereas morphine extends to a much greater dermatomal distribution.[3]

With this background, we aimed to find the effectiveness of intrathecal morphine and fentanyl as an adjuvant to isobaric ropivacaine in patients undergoing LSCS in terms of the mean duration of postoperative analgesia, block characteristics, and adverse effects.

Materials and Methods

This prospective, randomized, double-blinded observational study was conducted at a tertiary care center after obtaining approval from the institutional ethics committee (ref. no.: 2750/MC/EC/2016; dated: October 14, 2016) and written informed consent from all patients.

Parturients aged between 20 and 35 years of age, 40–80 kg of weight, more than 140 cm of height, belonging to American Society of Anaesthesiologist (ASA) physical status I and II, having uncomplicated singleton pregnancy, and scheduled for elective LSCS were enrolled in the study. Parturients with known complicated pregnancy, cardiovascular disease, diabetes mellitus, preeclampsia, and coagulopathies, allergic to study drugs, having contraindications to spinal anesthesia, and unwilling to participate were excluded from the study.

A total of 120 parturients were randomized into two groups of 60 parturients each, using a computer-generated randomization number table, and the allocated groups were maintained in sequentially numbered and sealed opaque envelopes. Parturients in Group M received 15 mg of 0.75% isobaric ropivacaine (2 mL) and 100 μg of morphine (1 mL). Parturients in Group F received 15 mg of 0.75% isobaric ropivacaine (2 mL) and 25 μg of fentanyl (0.5 mL) and 0.5 mL of normal saline; total volume was kept 3 mL in both groups to achieve blinding. The anesthesiologist involved in study drug preparation was different from the anesthesiologist performing spinal block. Both the parturient and anesthesiologist involved in recording of data were also blinded to the protocol used.

All the parturients were thoroughly examined preoperatively including history, general physical examination, and all routine investigation. The procedure was explained to the patients and a written informed consent was obtained. The concept of visual analog scale (VAS) score was explained to the patient in the preoperative area on the day of the surgery. After confirming fasting status, patient was shifted to the operation theatre. Multipara monitoring of electrocardiogram, noninvasive blood pressure (BP), and pulse oximeter was attached to the patient and base line parameters were recorded. A good IV access was secured with 18-G cannula. Parturients were premedicated with ranitidine 50 mg IV and metoclopramide 10 mg IV. Preloading was carried out by 15 mL/kg Ringer's lactate just before the administration of spinal block.

Under all aseptic precautions, spinal block was performed at the L3-L4/L4-L5 interspace using 25-G Quincke–Babcock spinal needle in sitting/left lateral decubitus position. A total volume of 3 mL was injected as per assigned group. Patient was placed in supine position immediately after spinal injection to achieve maximum level of block. Oxygen (4 L/min) was administered via a simple face mask. IV infusion was continued at a rate of 10 mL/kg/h throughout the surgery. Monitoring of heart rate (HR), systolic BP (SBP), diastolic BP (DBP), mean arterial BP (MAP), and peripheral oxygen saturation (SpO2) was carried out every 5 min for the first 30 min and thereafter every 10 min till the completion of the surgery.

Hypotension, defined as a fall in SBP level more than 20% from baseline or a fall below 90 mm Hg, was treated with IV fluid bolus and incremental IV doses of ephedrine 5 mg, if required. Bradycardia, defined as HR <60 bpm, was treated with IV atropine (0.3–0.6 mg).

The onset of sensory block was defined as the time from the intrathecal injection of the study drug to the time taken to achieve the highest level of sensory block. This was assessed by pinprick test bilaterally in midclavicular line by using a 25-G hypodermic needle. The level of sensory block was assessed every 2 min till the highest level of the block was reached, and the time to achieve the same was also noted. Regression of sensory block was defined as the time taken for the sensory block to regress up to two segments of dermatome from the highest level achieved.

Onset of motor block was defined as the time from the intrathecal injection of the study drug to the time taken to achieve complete motor block (grade 3) by using Bromage scale (0, no block; 1, able to flex knees with free movement of feet; 2, unable to flex knees but free movement of feet; 3, complete block). Duration of motor block was assessed by recording the time elapsed from the maximum to the lowest Bromage score (3–0).

Total duration of analgesia was taken as the time from intrathecal drug administration to patient's first demand of rescue analgesia (VAS score, 3).

Postoperatively, the pain was assessed by using visual analog pain scale (VAS) between 0 and 10 (0, no pain; 10, most severe pain). It was assessed at every 30 min. Parturients were allowed to receive rescue analgesic on VAS score of 3. IV injection diclofenac (75 mg) was given as rescue analgesic. This was the end point of our study.

Postoperative sedation level was measured by using the four-point sedation scale (1, spontaneous eye opening; 2, eyes open to speech; 3, eyes open when shaken; 4, not arousable).

Patient was monitored for 24 h for any adverse effects, such as nausea, vomiting, pruritus, headache, bradycardia, respiratory depression, and hypotension, and treated accordingly.

Sample size calculation was based on mean duration of analgesia. It was calculated to be, 52 subjects in each group, with the power of study at 80% and keeping the alpha error at 5% assuming the standard deviation was 3.3 (as per se ed article). So, for the study purpose 60 parturients were recruited in each group to compensate for dropouts. Statistical analysis was carried out using SPSS version 16.0. (SPSS Inc., Chicago, Illinois, U.S.A.). Quantitative data were represented as mean ± SD and qualitative data were expressed as percentage. Chi-square test was used for the analysis of qualitative data and unpaired t-test for quantitative data. P value <0.05 was taken as statistically significant.

Results

A total of 120 consented parturients scheduled for LSCS were randomized to two groups of 60 each. Both groups were comparable for their demographic data of age, weight, height, ASA physical status, and duration of surgery [Table 1]. Both groups were similar in the maximal dermatome height achieved.

Characteristics of sensory and motor block were comparable in both groups [Table 2]. Mean duration of analgesia in Group M and Group F was 996.03 ± 25.3 and 203.88 ± 25.20 min, respectively; the difference between the groups was highly significant (P < 0.0001).

Hemodynamic variables (HR, SBP, DBP, and MAP) were similar in the two groups during Pre, intra, and postoperative period [Figure 1] and [Figure 2]. Sedation score was 1.38 ± 0.58 in Group M and 1.30 ± 0.46 in Group F, this difference was not significant (P = 0.3883).

Figure 1: Trends of heart rate in intraoperative and postoperative period in both groups

In Group M, 6.67% patients had hypotension, 1.66% patients had bradycardia, 6.67% patients had shivering, 10% patients had nausea and vomiting, and 8.33% patients had pruritus, whereas in Group F, 10% patients had hypotension, 3.33% patients had bradycardia, 1.66% patients had shivering, 5% patients had nausea and vomiting, and 3.33% patients had pruritus. All these adverse effects were comparable between the two study groups. No patient experienced respiratory depression in any group [Figure 3].

Spinal administration of LA usually produces segmental analgesia by direct spinal action, blocking sodium channels to produce cell membrane depolarization. However, the most commonly used practice for spinal analgesia is to use mixture of LA and opioids because a supra-additive effect in the spinal cord posterior horn pain transmission mechanism is observed with this combination. In a review of combinations of opioid analgesics, it was suggested that the combination of LA and opioids improves analgesic efficacy with fewer side effects because of the interaction with the GPT-mediated signal transduction between calcium channels and opioid receptors.[4],[5]

Morphine is a long-acting, hydrophilic, natural opioid analgesic. It binds to high-affinity receptors in the dorsal horn receptor sites, but exhibits much lower capacity for binding to non-receptor sites in the myelin and white matter of the cord compared with fentanyl. This results in a small “volume of distribution” within the spinal cord and a sustained high concentration within the CSF. This accounts for the clinically observed wide band of analgesia and propensity for cephalic spread with the potential for late-onset respiratory depression.[6] Ropivacaine and morphine combination provides longer postoperative pain relief without significant side effects.[7]

Fentanyl is a synthetic lipophilic opioid with a rapid onset of action, has lesser tendencies to migrate rostrally to the fourth ventricle in sufficient concentration to cause delayed respiratory depression.[8] It is commonly used as an adjunct to intrathecal regional anesthesia and reduces visceral and somatic pain,[9] but is limited by dose-dependent adverse effects.

Onset of sensory and motor block, two-segment regression, and duration of motor block were comparable in both groups; this is in accordance with various studies.[7],[10],[11],[12]

In this study, we found that the addition of 100 μg morphine to 0.75% isobaric ropivacaine significantly prolongs the duration of analgesia as compared to fentanyl (P < 0.0001). VAS scores were comparable between both the study groups till 3 h postoperatively, later significantly lower pain scores were observed in morphine group as compared to fentanyl group till 24 h (P value < 0.001). Similar observations have been made in several other studies.[10],[11],[13],[14] In another study, fentanyl (25 μg) and morphine (200 μg) were added to hyperbaric or isobaric bupivacaine for spinal anesthesia in caesarean section. They concluded that VAS score was high in fentanyl group as compared to morphine group and intrathecal morphine provides a long duration of postoperative analgesia, but the duration gets longer when it is combined with plain bupivacaine instead of heavy bupivacaine.[15]

Our study reported a greater risk of nausea and vomiting with the intrathecal morphine as compared to fentanyl (10% vs. 5%) but without achieving significance (P = 0.49). The mechanism for intrathecal opioid-induced PONV is thought to involve cephalad migration of the opioid in CSF to opioid receptors in the area postrema.[16]

No significant difference in the incidence of pruritus between study groups was observed (P = 0.43). Pruritus is one of the common side effects of intrathecal morphine; it is more likely to occur in obstetrics patients, perhaps because of interaction of estrogen with opioid receptors.

Other reported adverse effects included hypotension, bradycardia, and shivering. These were comparable between study groups. Respiratory depression was not observed in any group. Regarding adverse effects, similar observations have been made in various other studies.[10],[13],[14]

Conclusion

We conclude that the 100-μg intrathecal morphine as an adjuvant to 0.75% isobaric ropivacaine provided prolonged duration of analgesia as compared to the 25-μg intrathecal fentanyl as an adjuvant to 0.75% isobaric ropivacaine in parturients undergoing LSCS under spinal anesthesia, without causing significant hemodynamic variation and adverse effects.